A hallmark of many types of B cell lymphoma is chromosomal translocation, one type of genomic rearrangement, involving one of the immunoglobulin (Ig) loci and a proto-oncogene. Recurrent c-myc translocation is a classical example, often with Igh or Igl as translocation partners. c-myc rearrangements are observed in several aggressive B cell lymphomas including Burkitt lymphoma (BL, >90%), diffuse large B-cell lymphoma (DLBCL, 7-14%), plasmablastic lymphoma (~50%) and others. The presence of c-myc rearrangements in these diseases has critical diagnostic and prognostic implications. For example, c-myc rearrangements are associated with a poor prognosis in DLBCL patients treated with chemotherapy (e.g. R- CHOP). Thus, it is highly significant to elucidate the mechanisms of genomic rearrangements of c-myc. Such mechanistic studies will not only contribute significantly to our basic understanding of DNA repair but also guide the translational applications such as diagnosing aggressive B cell lymphomas or developing better therapeutic strategies. In this application, we propose to elucidate how differential DNA repair mechanisms operate in distinct B cell subpopulations to influence the level of c-myc genomic instability. Previous studies of Igh-c-myc translocation have resulted in a much deeper understanding of translocation mechanism, e.g. the role of activation-induced deaminase (AID) in generating DNA double stranded breaks (DSBs) at both Ig and c-myc loci. However, these previous studies have not considered the influence of activation status or microenvironment of B cells on the outcome of DNA repair pathways. AID is a central player of antibody diversity via inducing point mutations or DSBs at Ig loci. How AID-initiated lesions are prevented from inducing genome-wide damage is not completely understood. Prior studies proposed a differential DNA repair mechanism that protects certain non-Ig loci such as c-myc from AID attack. However, determinants that regulate such protective mechanisms remain largely unknown. Our preliminary studies reveal a complex interplay between target sequence, DNA repair mechanism, and activation or differentiation status of B cells, which appears to coordinately regulate genome stability at c-myc locus. We propose to employ our novel and unique mouse model and new techniques to elucidate the mechanisms regulating the occurrence of DSBs at c-myc locus in different subpopulations of B cells.